The respiratory mucosal immune system (as other mucosal sites) must balance its response to pathogens while also regulating inflammatory immune cell mediated tissue damage. In the airways a failure to very tightly control immune response to a pathogen can result in chronic inflammation and tissue destruction. Both ineffective immune responses as well as an over zealous response are deleterious for the host. Information is now emerging that chronic inflammation can also impact on subsequent responses to future infection by the same, but importantly to an unrelated pathogen. The effect of infection history on the immune response cannot be ignored as repeated microbial exposure, shapes the immune system in its response later in life. Experimental and epidemiological evidence show, that infection with one pathogen and the ensuing immune response can influence the way the host responds to a second unrelated pathogen. Traditionally we ascribe a memory phenotype only to adaptive immunity. However evidence is now emerging to show that innate immune pathways may also remain altered long after infection resolution and that the innate immune system is in fact shaped by a history of infection of the host. Our long term goal is to define innate immune mechanisms that protect the respiratory mucosal surface from infection and the inflammatory consequences of infection. In the current application we propose to analyze how the history of innate immune response generated by a prior respiratory viral infection will likely impact on a subsequent bacterial infection in the lung. Specifically, we will evaluate the interaction between anti-viral and anti-bacterial immune responses in the lung using mouse adapted respiratory syncytial virus (RSV) and non-typeable Haemophilus influenzae (NTHI) a gram negative bacterium. Interactions between these two pathogens have direct relevance to otitis media a disease of young children and also to a disease of adults, chronic obstructive pulmonary disease (COPD) the fourth most common cause of death in the US. In a broader context, the interactions between viruses and bacteria are particularly important as they impact on many diseases such as pneumonia, sinusitis, otitis media, COPD and gastroenteritis. Identifying the molecules/pathways involved in increased susceptibility or protection against subsequent infections may have a significant impact on therapeutic strategies to tackle infectious diseases. We propose the following two Specific Aims: 1) to determine the impact on mucosal anti-NTHI immune responses in a host that has experienced an RSV infection in the lung and 2) to determine the impact on mucosal immune responses to a secondary RSV infection in a host that is undergoing an NTHI infection in the lung. The impact of infection history is of paramount importance as it helps shape the immune response. It is now well recognized that simultaneous or sequential viral-bacterial infections often occur. Further, the innate responses provoked by the viral infection can modulate innate immunity to the subsequent bacterial infection. We will study the interplay between innate and adaptive immune responses against two pathogens that infect the respiratory mucosa.